1. Field of the Invention
The present invention relates to analgesic compounds targeted to the ORL1 receptor. More specifically, the present invention relates to agonist and antagonist compounds targeted to the ORL1 receptor and methods for their use.
2. Description of Related Art
It has been estimated that as much as 30% of the population of the industrialized countries of the world suffers from some degree of chronic pain. Many individuals suffering from chronic pain are forced to incur significant direct medical and pharmaceutical expenses. Such individuals often also suffer losses in income and productivity. In the United States, it is estimated that the combined value of these losses and costs is in excess of $50 billion annually.
To address the pain experienced by these millions of individuals, a large industry has developed to provide medications for controlling pain. The market for these analgesic drugs, broadly classified as nonsteroidal anti-inflammatory drugs and opiates, has become the largest in the world, with sales revenues estimated to be as high as 4.4 billion in 1996.
The analgesics sold in this market are among the most widely used compounds in the history of medicine. These products come in many forms, and include natural compounds and synthetic compounds which work safely and with varying degrees of effectiveness to ease the impact of pain on an individual. Many of the compounds used for severe pain are opiates such as morphine and synthetic morphine analogs. These compounds have become widely used and understood.
Despite their effectiveness against severe pain, opiate compounds are administered with caution, and their use is often restricted to relatively short time periods as a result of the side-effects and limitations often connected with their use. Many patients experience gastrointestinal side-effects which limit their ability to tolerate the medication for long periods of time. Other patients develop tolerance to opiates over time, resulting in diminished relief when opiate use is prolonged. Additionally, opiates carry a high potential for addiction, thus further endangering a patient. Accordingly, a need exists for effective, nonaddicting analgesic compounds which cause few, if any, undesirable side effects.
Opiates include a large class of compounds that act on opiate receptors, thus modulating the pain response in an individual. Three main subclasses of opiate receptors have been identified through binding studies, in vitro and in vivo pharmacology, autoradiography, and receptor cloning. Evans et al., Science, 258:1952-1955 (1992); Kieffer et al., Proc. Natl. Acad. Sci. USA, 89:12048-12052 (1992); Chen et al., Mol. Pharmacol., 44:8-12 (1993); Wang et al., Proc. Natl. Acad. Sci. USA, 90:10230-10234 (1993); and Yasuda et al., Proc. Natl. Acad. Sci. USA, 90:16736-16740 (1993). The μ, δ, and κ receptors are the apparent receptors acted upon by common opiate drugs.
During research aimed at characterizing opioid receptors, a closely-related orphan receptor eventually designated opioid receptor like 1 (“ORL1”) was identified. Mollereau et al., FEBS Lett., 341:33-38 (1994); Wang et al., FEBS Lett., 348:75-79 (1994); Bunzow et al., FEBS Lett., 347:284-288 (1994). Despite levels of homology with the μ, δ, and κ receptors similar to their own homology to each other, the ORL1 receptor failed to bind opiate compounds with high affinity. Although etorphine and some dynorphin gene products do produce a 1000-fold higher-than-expected response when exposed to ORL1, ORL1's failure to bind with other opiates demonstrates that though ORL1 is in the opiate receptor family, it is not a true opiate receptor. Zhang and Yu, J. Biol. Chem., 270:22772-22776 (1995).
In 1995, an endogenous ligand for ORL1 was sequenced. Meunier et al., Nature, 377:532-555 (1995). The peptide ligand, called nociceptin, is a 17-amino-acid peptide with a sequence resembling that of some opioid peptides, including dynorphin. Nociceptin was shown to inhibit cAMP accumulation in CHO cells transfected with ORL1, while causing no change in non-transfected parent cells.
In other studies, nociceptin showed low affinity for the μ, δ, and κ opioid receptors. Gintzler et al., Eur. J. Pharmacol., 325:29-34 (1997). Nociceptin also stimulates [35S] GTPγS binding in transfected cells and inhibits electrically-induced contractions in mouse vas deferens (MVD); and, to a lesser extent, in guinea pig ileum (GPI). Berzetei-Gurske et al., Eur. J. Pharmacol., 302:R1-R2 (1996). Further studies showed that intracerebroventricular injections of nociceptin decreases hot plate escape jumping latency and a decrease in tail flick latency in mice. Meunier et al., Nature, 377:532-555 (1995); and Reinscheid et al., Science, 270:792-794 (1995).
Intrathecal administration of nociceptin also shows promising use. When administered to the spinal cord in the presence of morphine, the action of morphine is inhibited, and further, nociceptin has analgesic action in tail flick testing in mice and also increases morphine analgesia. Tian et al., Br. J. Pharmacol., 120:676-680 (1997). Nociceptin has also been shown to be involved in peripheral analgesia, inhibiting formalin pain when administered intrathecally. Yamamoto et al., Neurosci., 81:249-254 (1997). It similarly acts analgesically when administered to rats in a hot plate test of rats with a chronic constriction injury, a model of neuropathic pain. Yamamoto et al., Neurosci. Lett., 224:107-110 (1997). Similar function was observed in models of chronic pain, and in diabetic mice. Kamei et al., Eur. J. Pharmacol., 370:109-116 (1999).
The results of these and other tests suggest that agonists of the nociceptin receptor may prove useful as non-opioid analgesics, potentially useful with neuropathic pain. Additionally, the results suggest that antagonists of the nociceptin receptor may likely exhibit anti-anxiety properties. Unfortunately, however, nociceptin, the natural ligand for ORL1, is difficult to administer to a patient, and once administered, nociceptin is very susceptible to the action of proteases. Accordingly, a need exists for compounds which act as agonists and antagonists of the ORL1 receptor that are more easily administered to a patient, and that are resistant to protease activity.
In more recent years, the pain medication market has expanded very rapidly with the entry of COX-II inhibitors for use with arthritic pain. The novel NSAID medications Vioxx® made by Merck Inc., and Celebrex® made by Pfizer/Pharmacia have garnered huge popularity and widespread use in combating pain. The sales of Celebrex® in 2001 alone were 3.1 billion dollars. These drugs have been shown to avoid some of the gastrointestinal problems of traditional NSAIDS while providing good relief to patients. Some researchers remain concerned about the prospective cardiovascular side-effects of these drugs, however. Additionally, as with opioid medications, these NSAIDS are generally ineffective against neuropathic pain. Neuropathic pain is a condition often thought to stem from damage to nerves, and is often found in diabetic patients. As diabetes levels continue to swell in the United States, it becomes obvious that a need exists for novel compounds which are effective against neuropathic pain which are not found in the current analgesic market.
Most known analgesic compounds are agonists of at least one of a group of opioid receptors. These compounds bind to the receptor, stimulating pain relief. Other known compounds share a similar structure, but merely compete for binding with agonist compounds. These competitive compounds are referred to as antagonists. Antagonist compounds often exhibit anxiety-relieving, or “anxiolytic” properties when administered to a patient. The high incidence of anxiety disorders suggests that it would be a benefit to characterize novel anxiolytic compounds.
Finally, recent research has shown that some compounds currently used for their analgesic properties also exhibit anti-cancer activity. Despite recent advances in medical technology and breakthroughs in molecular medicine, cancer remains a difficult disease to treat. As a result, any novel compound with anti-cancer properties is a welcomed improvement in the art.
Thus, it would be an improvement in the art to provide compounds including agonists and antagonists of the ORL1 receptor. Further, it would be a benefit to provide novel compounds for use as analgesics. Similarly, it would be an improvement in the art to provide novel compounds for use as anxiolytic agents. It would also be an improvement to provide novel compounds with anti-cancer properties.
Such compounds and methods of their use are disclosed herein.